Model for receptor activation.

<p>The cytokine and ECDs of the two receptor molecules are colored in the same scheme as in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002427#pcbi-1002427-g001" target="_blank">Figure 1</a>. The ECD-TMH linkers are represented by red lines, and the TMHs are represented by lime green coils. Residue Cys241 in GHR is at the midpoint of the ECD-TMH linker. The ICDs are in turquoise green and JAK2s are in yellow. (A) In the preformed dimer, the two ECDs are apart, but the TMHs and ICDs are in contact; the associated JAK2s are oriented away from each other. (B) The cytokine binds to R1 via site 1 to form the 1∶1 complex. (C) R2 approaches site 2 of the cytokine in the 1∶1 complex, resulting in a loose complex in which the N-terminal subdomains of the two ECDs are nearly anti-parallel and the membrane-proximal ends of the two C-terminal subdomains are apart. (D) Scissor-like rotation of R1 and R2 leads to separation of the ICDs, making room for the JAK2s to approach each other. Self-rotation of R2 (and R1 to a lesser extent) further allows the JAK2s to orient properly for transphosphorylation.